The association of different classes of substances presenting antihelminthic actions aims to combat an increasing resistance of parasites to most of the drugs used. The resistance of parasites to different classes of antihelminthic drugs has been reported since early use of these drugs. The resistance for benzimidazole is all over the world. Studies have been reported, mainly related to three main species of bovine's parasites: Ostertagia, Trichostrongylus, Cooperia. Although parasites resistance to levamisole is well known, it is much more restrict than to benzimidazoles. Resistance and crossed resistance reports have been reported, mainly to Cooperia species.
The strategy to combat this resistance has been trying to avoid the indiscriminate use of antihelminthic drugs, to alternate drugs during treatment and to use potential number of parasites which survive the treatment. The association of active principles aiming a synergetic function among them is a well known strategy, mainly in the treatment of pathogenic agents with bacteria, protozoans, fungus, and parasites. A real synergism occurs when the association of two or more pharmaceutical actives is higher than all individual actions together.
The aim of this invention is to describe the use of organic salts of levamisole associated to avermectins and/or milbemycins in the combat to helminthiasis.
Levamisole (L-2,3,5,6-tetrahydro-6-phenil-imidazo-[2,1-b]thiazole), it is an antiparasitary widely used for intestinal control of nematodes and respiratory worms in some animals. Due to its basic characteristic, it forms salts with organic and inorganic acids, depending on pka of this acid.
Antiparasitaries such as disophenol (2,6-dilodo-4-nitrophenol) and nitroxinil (4-hydroxy-3-iodo-5-nitrobenzonitrile), which are used to control trematodes and some nematodes, produce a salt with levamisole under some conditions due to its acid characteristic of phenol group of these molecules. The description, obtainment, and use of levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile were described in the patent GB 2150024 A. Levamisole salt of 2,6-diiodo-4-nitrophenol and levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile from now on will be referred only as levamisole organic salts, when suitable.
Avermectins, a compound which belongs to macrocyclic lactones, are powerful antiparasitary agents which are used to combat parasites in mammals. They are secondary metabolic produced by Streptomyces avemitilis, obtained through a fermenting process. Some avermectins are obtained in a semi synthetic composition as ivermectin, which is obtained through abamectin hydrogenization. A series of compounds denominated avermectins are abamectin, doramectin, eprinomectin, ivermectin and selamectin.
Milbemycins are similar to avermectins in their structure, because they have a 16 membered ring structures. However, it does not have a disaccharidic sub unit and there are constituent differences. Milbemycin used in the association are selected from the group consisting of moxidectin, milbemycin and milbemycin oxime.
Considering these aspects, it is known that levamisole salt of 2,6-diiodo-4-nitrophenol, as well as levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile, both combine the action of levamisole against nematodes, for example, Haemonchus contortus, Ostertagia spp., Trichostrongylus spp. (example: Trichostrongylus axei), Cooperia spp. (Cooperia oncophora), Nematordirus spp. (example: Oesaphagostomum venulosum), Strongyloides spp. (example: Strongyloides papillosus), Bunostomum spp. (ex: Bunostomum trigonocephalum), Chabertia spp (ex: Chabertia ovina), Trichuris spp. (ex: Trichuris ovis) and Dictyocaulus spp. (ex: Dictyocaulus filaria and Dictyocaulus viviparous) with the action of disophenol or nitroxinil against trematodes, for example, Fasciola hepatic and gigantic Fasciola, and some nematodes, for example, Haemonchus contortus, Bunostomum spp. Oesaphagostomum spp., Parafilaria bovicola. Considering that levamisole presents a low action against Ostertagia parasites and a good action against Cooperia class, and avermectins and milbemycin has a good inverse action, which means low action against Cooperia and good action against Ostertagia, a combination of actions of levamisole salt of 2,6-diiodo-4-nitrophenol and levamisole salt of 4-hydroxy-3-iodo-5-nitrobenzonitrile with avermectins and milbemycins, aiming a wide spectrum formulation against parasites, besides a synergism of actions among actives. In such case, this association maybe indicated as a parasiticide in the treatment of nematodes, cestodes, and trematodes in bovines, swine, caprines, equines, ovines, canines and felines.
Associations of avermectins and levamisole have already been described before, in patent WO 00061068 and in patent application WO 2004/009080 A1. The greatest discovery in the study is the use of salts of levamisole, which besides levamisole action they present fascioliscide action, when associated with avermectins. Other associations with fascioliscide compounds were proposed in documents WO 95/05812 and GB 2386067A, both describing the association of avermectins and milbemycins with closantel.